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Background and Aims: We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation., Methods: From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors., Results: We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy., Conclusions: The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/aims: Hepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive., Methods: Data from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%)., Results: Serum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00-1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48-3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05-1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000-1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006-1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52-4.45, P < 0.001)., Conclusions: The HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes., Competing Interests: Declaration of competing interest Ming-Lung Yu. Research support from Abbvie, Abbott, BMS, Gilead, Merck and Roche. Consultant for Abbvie, Abbott, Ascletis, BMS, Gilead, J&J, Merck, Novartis, Pharmaessential and Roche. Speaker for Abbvie, Abbott, Ascletis, BMS, Gilead, Merck, Pharmaessential and Roche. Chung-Feng Huang. Speaker for Abbvie, BMS, Gilead, Merck, and Roche., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/aims: Steatotic liver disease (SLD) is a common manifestation in chronic hepatitis C (CHC). Metabolic alterations in CHC are associated with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to elucidate whether hepatitis C virus (HCV) eradication mitigates MASLD occurrence or resolution., Methods: We enrolled 5,840 CHC patients whose HCV was eradicated by direct-acting antivirals in a nationwide HCV registry. MASLD and the associated cardiometabolic risk factors (CMRFs) were evaluated at baseline and 6 months after HCV cure., Results: There were 2,147 (36.8%) patients with SLD, and 1,986 (34.0%) of them met the MASLD criteria before treatment. After treatment, HbA1C (6.0% vs. 5.9%, P<0.001) and BMI (24.8 kg/m2 vs. 24.7 kg/m2, P<0.001) decreased, whereas HDL-C (49.1 mg/dL vs. 51.9 mg/dL, P<0.001) and triglycerides (102.8 mg/dL vs. 111.9 mg/dL, P<0.001) increased significantly. The proportion of patients with SLD was 37.5% after HCV eradication, which did not change significantly compared with the pretreatment status. The percentage of the patients who had post-treatment MASLD was 34.8%, which did not differ significantly from the pretreatment status (P=0.17). Body mass index (BMI) (odds ratio [OR]/95% confidence intervals [CI]: 0.89/0.85-0.92, P<0.001) was the only factor associated with MASLD resolution. In contrast, unfavorable CMRFs, including BMI (OR/CI: 1.10/1.06-1.14, P<0.001) and HbA1c (OR/CI: 1.19/1.04-1.35, P=0.01), were independently associated with MASLD development after HCV cure., Conclusions: HCV eradication mitigates MASLD in CHC patients. CMRF surveillance is mandatory for CHC patients with metabolic alterations, which are altered after HCV eradication and predict the evolution of MASLD.

Background and Aim: Among low viral load (DNA of hepatitis B virus (HBV) was < 2000 IU/mL), the factor of the loss of hepatitis B surface antigen (HBsAg) remained elusive., Methods: The retrospective study recruited patients with chronic hepatitis B (CHB) who were negative low for hepatitis B e-antigen (HBeAg), had a low viral load, and experienced HBsAg loss during follow-up. CHB patients with low-viral load but without consequent HBsAg loss were also enrolled at the ratio of 1:4. The factors contributing to HBsAg loss were analyzed., Results: A total of 80 patients were recruited for the current study, with a mean age of 63.9 years and 61.3% being male. Among them, 62.5% patients (50/80) were treated with potent nucleoside/nucleotide analogues (NAs) during the follow-up period. Additionally, 12.5% patients (10/80) had a prior history of NAs treatment before enrolment. During the follow-up, HBsAg loss occurred in 17 patients (21.3%). Compared with patients without HBsAg loss, those with HBsAg loss were younger (57.9 years vs 65.5 years; P = 0.01), had lower HBV DNA levels (1.3 log 10 IU/mL vs 2.3 log 10 IU/mL; P = 0.003), and higher proportion of prior NAs-treated history. Logistic regression analysis revealed that the factors associated with factors associated with HBsAg loss were age < 60 years (OR/CI: 3.95/1.15-13.60, P = 0.03), prior NAs-treated history (OR/CI: 7.59/1.42-40.51, P = 0.01) and current NAs-treated (OR/CI: 0.19/0.05-0.71, P = 0.01)., Conclusions: In the study, older age and prior NAs were positively associated with HBsAg loss, and current NAs was negatively associated with HBsAg loss. Additionally, some patients experienced HBsAg loss during the NAs therapy., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The tailor-made synthetic sRNA-based gene expression knockdown system has demonstrated its efficacy in achieving pathway balancing in microbes, facilitating precise target gene repression and fine-tuned control of gene expression. This system operates under a competitive mode of gene regulation, wherein the tailor-made synthetic sRNA shares the intrinsic intracellular Hfq protein with other RNAs. The limited intracellular Hfq amount has the potential to become a constraining factor in the post-transcription regulation of sRNAs. To enhance the efficiency of the tailor-made sRNA gene expression regulation platform, we introduced an Hfq expression level modulation-coordinated sRNA-based gene knockdown system. This system comprises tailor-made sRNA expression cassettes that produce varying Hfq expression levels using different strength promoters. Modulating the expression levels of Hfq significantly improved the repressing capacity of sRNA, as evidenced by evaluations with four fluorescence proteins. In order to validate the practical application of this system, we applied the Hfq-modulated sRNA-based gene knockdown cassette to Escherichia coli strains producing 5-aminolevulinic acid and L-tyrosine. Diversifying the expression levels of metabolic enzymes through this cassette resulted in substantial increases of 74.6% in 5-aminolevulinic acid and 144% in L-tyrosine production. Tailor-made synthetic sRNA-based gene expression knockdown system, coupled with Hfq copy modulation, exhibits potential for optimizing metabolic fluxes through biosynthetic pathways, thereby enhancing the production yields of bioproducts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aim: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear., Methods: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF., Results: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups., Conclusions: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The immune response of patients with chronic liver disease tends to be lower after receiving their second coronavirus disease 2019 (COVID-19) vaccine dose, but the effect of a third vaccine dose on their immune response is currently unknown. We recruited 722 patients without previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from three hospitals. The patients received homologous (MMM) and heterologous (AZAZBNT, AZAZM) boosters, where AZ, BNT, and M denoted the AZD1222, BNT162b2, and mRNA-1273 vaccines, respectively. Serum IgG spike antibody levels were measured at a mean 1.5 ± 0.7 (visit 1) and 5.0 ± 0.5 (visit 2) months after the third vaccine booster. A threshold of 4160 AU/mL was considered significant antibody activity. In both visits, the patients who received the MMM booster had higher anti-S-IgG levels than those who received the AZAZBNT and AZAZM boosters. Patients with active hepatocellular carcinoma (HCC) had lower anti-S-IgG levels than the control group (761.6 vs. 1498.2 BAU/mL; p = 0.019) at visit 1. The anti-S-IgG levels decreased significantly at visit 2. The patients with significant antibody activity had a lower rate of liver cirrhosis with decompensation (0.7% decompensation vs. 8.0% non-decompensation and 91.3% non-liver cirrhosis, p = 0.015), and active HCC (1.5% active HCC vs. 3.7% non-active HCC and 94.7% non-HCC, p < 0.001). Receiving the MMM booster regimen (OR = 10.67, 95% CI 5.20-21.91, p < 0.001) increased the odds of having significant antibody activity compared with the AZAZBNT booster regimen. Patients with active HCC had a reduced immune response to the third COVID-19 vaccine booster. These findings underscore the importance of booster vaccinations, especially in immunocompromised patients, with superior efficacy observed with the homologous mRNA-1273 regimen., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Dysregulation of cancer cell motility is a key driver of invasion and metastasis. High dysadherin expression in cancer cells is correlated with invasion and metastasis. Here, we found the molecular mechanism by which dysadherin regulates the migration and invasion of colon cancer (CC). Comprehensive analysis using single-cell RNA sequencing data from CC patients revealed that high dysadherin expression in cells is linked to cell migration-related gene signatures. We confirmed that the deletion of dysadherin in tumor cells hindered local invasion and distant migration using in vivo tumor models. In this context, by performing cell morphological analysis, we found that aberrant cell migration resulted from impaired actin dynamics, focal adhesion turnover and protrusive structure formation upon dysadherin expression. Mechanistically, the activation of focal adhesion kinase (FAK) was observed in dysadherin-enriched cells. The dysadherin/FAK axis enhanced cell migration and invasion by activating the FAK downstream cascade, which includes the Rho family of small GTPases. Overall, this study illuminates the role of dysadherin in modulating cancer cell migration by forcing actin dynamics and protrusive structure formation via FAK signaling, indicating that targeting dysadherin may be a potential therapeutic strategy for CC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The accuracy of noninvasive seromarkers in predicting liver fibrosis in metabolic dysfunction-associated fatty liver disease (MAFLD) patients with or without viral hepatitis is elusive. The AST to platelet ratio index (APRI), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) were assessed in 871 MAFLD patients who received elastography in a viral hepatitis-endemic area. The area under the receiver operating characteristic (AUROC) curve increased substantially with increasing fibrotic stage across the three biomarkers. APRI (AUROC range 0.73-0.80) and FIB-4 (AUROC range 0.66-0.82) performed better than NFS (AUROC range 0.63-0.75). When patients were divided into viral and non-viral MAFLD groups, a better AUROC of APRI (range 0.76-0.80) and FIB-4 (range 0.68-0.78) than NFS (range 0.62-70) existed only in viral MALFD but not in non-viral MAFLD. Regarding the NFS, the AUROC was higher in non-viral MAFLD (range 0.69-0.86) and outperformed viral MAFLD at all fibrotic stages. The accuracy in predicting liver fibrosis increased with the advancement of liver disease for the three biomarkers. NFS exerted better diagnostic accuracy in non-viral than in viral MAFLD patients across different fibrotic stages. The best accuracy was 91.1% using the cutoff value of -9.98 for the NFS in predicting liver cirrhosis in non-viral MAFLD patients. The APRI and FIB-4 performed better than the NFS in predicting liver fibrosis in MAFLD as a whole. The suboptimal performance and accuracy of the NFS existed only in viral MAFLD patients. Caution should be taken when assessing the NFS in MAFLD patients with viral hepatitis., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: Air pollution is a risk factor for hepatocellular carcinoma (HCC). However, the effect of air pollution on HCC risk in patients with hepatitis remains unclear., Methods: This cross-sectional study recruited 348 patients with chronic hepatitis who were tested for serum hepatitis B surface antigen (HBsAg) and for antibodies against hepatitis B core antigen (HBcIgG) and hepatitis C virus (anti-HCV) in 2022. The diagnosis of HCC was based on the International Classification of Diseases, 10th revision (ICD-10). Daily estimates of air pollutants were aggregated into mean estimates for the previous year based on the date of recruitment or HCC diagnosis., Results: Out of 348 patients, 12 had HCC (3.4%). Patients with HCC were older (71.7 vs 50.9 years; p = 0.004), had higher proportion of HBsAg seropositivity (41.7% vs 5.1%; p < 0.001), and substantially higher levels of particulate matter 2.5 (PM 2.5 ) (21.5 vs 18.2 μg/m 3 ; p = 0.05). Logistic regression analysis revealed that the factors associated with HCC were age (odds ratio [OR]: 1.10; CI, 1.03-1.17; p = 0.01), PM 2.5 level (OR: 1.51; CI, 1.02-2.23; p = 0.04), and HBsAg seropositivity (OR: 6.60; CI, 1.51-28.85; p = 0.01) ( Table 3 ). There was a combined effect of PM 2.5 and HBsAg seropositivity on the risk of HCC development (OR: 22.17; CI, 3.33-147.45; p = 0.001)., Conclusion: In this study, we demonstrated that PM 2.5 and HBsAg seropositivity were associated with HCC occurrence and had synergistic effects after adjusting for confounding factors., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti-HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 μm in diameter [PM 2.5 ], nitrogen dioxide [NO 2 ], ozone [O 3 ] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05-4.77; p < 0.001), smoking (OR, 1.79; 95% CI, 1.16-2.74; p = 0.01), age (OR, 1.04; 95% CI, 1.02-1.05; p < 0.001) and PM 2.5 (OR, 1.10; 95% CI, 1.05-1.16; p < 0.001). Linear regression analysis revealed that LSM was independently correlated with PM 2.5 (β: 0.134; 95% CI: 0.025, 0.243; p = 0.02). There was a dose-dependent relationship between different fibrotic stages and the PM 2.5 level (the PM 2.5 level in patients with fibrotic stages 0, 1-2 and 3-4: 27.9, 28.4, and 29.3 μg/m 3 , respectively; trend p < 0.001). Exposure to PM 2.5 , as well as HBV and HCV infections, is associated with advanced liver fibrosis in patients with MAFLD. There was a dose-dependent correlation between PM 2.5 levels and the severity of hepatic fibrosis., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Elevated serum gamma-glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month-6) after initiating NAs were measured to explore their association with all-cause, liver-related, and non-liver-related mortality. The annual incidence of all-cause mortality was 0.9/100 person-years over a follow-up period of 17,436.3 person-years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month-6-GGT levels (62.1 vs. 38.4 U/L, p < 0.001). The factors associated with all-cause mortality included cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 2.66/1.92-3.70, p < 0.001), pretreatment GGT levels (HR/CI: 1.004/1.003-1.006, p < 0.001), alanine aminotransferase level (HR/CI: 0.996/0.994-0.998, p = 0.001), and age (HR/CI: 1.06/1.04-1.07, p < 0.001). Regarding liver-related mortality, the independent factors included cirrhosis (HR/CI: 4.36/2.79-6.89, p < 0.001), pretreatment GGT levels (HR/CI: 1.006/1.004-1.008, p < 0.001), alanine aminotransferase level (HR/CI: 0.993/0.990-0.997, p = 0.001), age (HR/CI: 1.03/1.01-1.05, p < 0.001), and fatty liver disease (HR/CI: 0.30/0.15-0.59, p = 0.001). Pretreatment GGT levels were also independently predictive of non-liver-related mortality (HR/CI: 1.003/1.000-1.005, p = 0.03). The results remained consistent after excluding the patients with a history of alcohol use. A dose-dependent manner of <25, 25-75, and >75 percentile of pretreatment GGT levels was observed with respect to the all-cause mortality (trend p < 0.001). Pretreatment serum GGT levels predicted all-cause, liver-related, and non-liver-related mortality in patients with CHB treated with NAs., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background and Aims: Fatty liver disease (FLD) is associated with several metabolic derangements. We conducted a retrospective cross-sectional and longitudinal study to evaluate the role of FL severity in the risk of new-onset and co-existing hypertension (HTN) and diabetes mellitus (DM)., Methods: The cross-sectional cohort consisted of 41,888 adults who received health checkups in a tertiary hospital of Taiwan from 1999 to 2013. Of them, 34,865 without HTN and/or DM at baseline and within 1 year after enrollment were included as a longitudinal cohort (mean, 6.45 years for HTN; 6.75 years for DM). FL severity based on the degree of hepatic steatosis was assessed by ultrasound sonography., Results: In cross-sectional cohort, 22,852 (54.6%) subjects had FL (18,203 [43.46%] mild FL and 4,649 [11.10%] moderate/severe FL); 13.5% (n = 5668) had HTN; and 3.4% (n = 1411) had DM. Moderate/severe FL and mild FL had significantly higher risks of existing HTN (adjusted odds ratio/95% confidence interval [CI] 1.59/1.43-1.77 and 1.22/1.13-1.32, respectively). In longitudinal cohort, 3,209 and 822 subjects developed new-onset HTN and DM, respectively (annual incidence, 14.3 and 3.5 per 1000 person-years; 10-year cumulative incidence, 14.35% and 3.89%, respectively). Moderate/severe and mild FL had significantly higher risks of new-onset HTN (adjusted hazard ratio [aHR]/CI 1.54/1.34-1.77 and 1.26/1.16-1.37, respectively) and DM (aHR/CI 5.88/4.44-7.81 and 3.22/2.56-4.07, respectively). Resolved FL during follow-up decreased the risk of HTN and/or DM., Conclusions: Patients with FL are at high risk of prevalent and incident HTN and/or DM. The risk increases with the severity of FL., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background and Aim: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its interplay with hepatitis B virus (HBV) and hepatitis C virus (HCV) in terms of liver disease severity is elusive., Methods: A mass surveillance program was conducted in a viral hepatitis endemic area. The objective was to identify MAFLD/non-MAFLD subjects with advanced liver disease., Results: Two thousand two hundred and forty-two (41.7%) of the 5378 subjects were identified as having MAFLD, and 375 (7.0%) had advanced liver disease. The proportions of anti-HCV and HBsAg seropositivity were 19.3% and 9.7%, respectively. The proportions of advanced fibrosis in subjects with non-viral hepatitis (NBNC), HBV and HCV infection were 2.8%, 5.7% and 23.4%, respectively. Subjects with MAFLD had a significantly higher proportion of advanced fibrosis (8.7% vs 5.7%, P < 0.001). Factors associated with advanced fibrosis included age (odds ratio [OR]/95% confidence interval [CI]: 4.8/3.7-6.0, P < 0.001), male sex (OR/CI: 1.3/1.0-1.7, P = 0.019), anti-HCV seropositivity (OR/CI: 5.9/4.6-7.5, P = 0.019), MAFLD-lean metabolic dysregulation (MS) (OR/CI: 2.6/1.3-5.2, P = 0.005; compared with the non-MAFLD group) and MAFLD-diabetes (OR/CI: 1.5/1.1-2.1, P = 0.008; compared with the non-MAFLD group). MAFLD did not aggravate liver disease severity in patients with viral hepatitis. However, among NBNC subjects, factors associated with advanced liver disease included MAFLD-lean MS group (OR/CI: 9.1/2.4-34.6, P = 0.001; compared with non-MAFLD group) and MAFLD-DM group (OR/CI: 2.0/1.2-3.2, P = 0.004; compared with non-MAFLD group)., Conclusions: MAFLD patients with diabetes and metabolic dysregulation had a higher risk of advanced liver disease. The effect was more significant in non-viral hepatitis subjects in a community level., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti-HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post-treatment follow-up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy-three (4.9%) individuals were seropositive for anti-HCV antibodies. Of the 73 anti-HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty-three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post-treatment follow-up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient-centered and integrated outreach program facilitated HCV care in this marginalized population., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Unawareness of hepatitis B virus (HBV) infection and lack of surveillance may serve as major barriers to HBV control and contributors to severe hepatocellular carcinoma (HCC) at presentation. This study evaluated the risk of HBV unawareness and its relationship with HCC severity. This retrospective study was conducted in a tertiary hospital in Taiwan. Patients with HBV-related HCC diagnosed from 2011 to 2021 were enrolled. The demographic, clinical, and HCC characteristics were collected and compared between patients with HBV unawareness and awareness with and without surveillance. Of 501 HBV-related HCC patients enrolled, 105 (21%) patients were unaware of HBV infection at the time of HCC diagnosis. Patients with HBV unawareness were significantly younger and had poorer liver function than those with HBV awareness. Patients with HBV unawareness also had a significantly higher rate of detectable HBV DNA and an advanced stage of HCC. Ninety-one (23%) of the HBV-aware patients did not receive regular surveillance. Patients with HBV unawareness and awareness without surveillance shared similar clinical characteristics with more severe HCC status. Further regression analysis demonstrated that HBV awareness with periodic surveillance was associated with early stage HCC. Meanwhile, we observed that there was no change in the proportion of HBV awareness over the past 10 years. Patients with surveillance also had better HCC survival than patients without surveillance or unawareness. HBV unawareness and lack of regular surveillance correlated with advanced HCC at presentation. Efforts to improve HBV education, disease awareness, and HCC surveillance are needed., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background and Aims: Disease severity across the different diagnostic categories of metabolic dysfunction-associated fatty liver disease (MAFLD) remains elusive. This study assessed the fibrosis stages and features of MAFLD between different items. We also aimed to investigate the associations between advanced fibrosis and risk factors., Methods: This multicenter cross-sectional study enrolled adults participating in liver disease screening in the community. Patients were stratified following MAFLD diagnostic criteria, to group A (395 patients) for type 2 diabetes, group B (1,818 patients) for body mass index (BMI)>23 kg/m 2 , and group C (44 patients) for BMI≤23 kg/m 2 with at least two metabolic factors. Advanced fibrosis was defined as a fibrosis-4 index>2.67., Results: Between 2009 and 2020, 1,948 MAFLD patients were recruited, including 478 with concomitant liver diseases. Advanced fibrosis was observed in 125 patients. A significantly larger proportion of patients in group C (25.0%) than in group A (7.6%) and group B (5.8%) had advanced fibrosis ( p <0.01). Logistic regression analysis found that hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection (odds ratio [OR]: 12.14, 95% confidence interval [CI]: 4.04-36.52; p <0.01), HCV infection (OR: 7.87, 95% CI: 4.78-12.97; p <0.01), group C (OR: 6.00, 95% CI: 2.53-14.22; p <0.01), and TC/LDL-C (OR: 1.21, 95% CI: 1.06-1.38; p <0.01) were significant predictors of advanced fibrosis., Conclusions: A higher proportion of lean MAFLD patients with metabolic abnormalities had advanced fibrosis. HCV infection was significantly associated with advanced fibrosis., Competing Interests: Jee-Fu Huang: Consultant of Roche, BMS, Gilead, Merck, Sysmex, Pharmaessential, Polaris, Aligos, and Instylla. Speaker for Abbvie, BMS, Gilead, Merck, Sysmex, and Roche. Editorial board member of Journal of Clinical and Translational Hepatology since 2022. Chia-Yen Dai: Consultant of Abbvie and Roche; Speaker for Abbvie, Gilead, and Roche. Chung-Feng Huang: Speaker for Abbvie, BMS, Bayer, Gilead, Merck, and Roche. Ming-Lung Yu: Research grant from Abbott, BMS, Merck, and Gilead; Consultant of Abbvie, Abbott, Ascletis, BMS, Merck, Gilead, and Roche; Speaker for Abbvie, Abbott, BMS, Merck, Gilead, and IPSEN. Editorial board member of Journal of Clinical and Translational Hepatology since 2023. Wan-Long Chuang: Consultant of Gilead, AbbVie, BMS, PharmaEssentia, and Aligos; Speaker for Gilead, AbbVie, BMS, and PharmaEssentia. Editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)

Biochemical response is an important prognostic indicator in chronic hepatitis B (CHB) patients receiving nucleotide/nucleoside analogues (NAs). However, the effects of air pollution in alanine aminotransferase (ALT) normalization remain elusive. This longitudinal study recruited 80 hepatitis B e antigen-negative CHB patients who received NAs. ALT levels were measured during the first year of anti-hepatitis B virus therapy. Normal ALT levels were defined as <19 U/L for females and <30 U/L for males, and the risk factors associated with ALT abnormalities were analyzed. The daily estimations of air pollutants (particulate matter ≤2.5 µm in diameter (PM2.5), nitrogen dioxide, ozone (O3), and benzene) were aggregated into the mean estimation for the previous month based on the date of recruitment (baseline) and 1 year later. Sixteen patients (20.0%) had a baseline ALT > 40 U/L; overall, 41 (51.6%) had an abnormal ALT (≥19 U/L for females and ≥ 30 U/L for males). After 1 year of NA therapy, 75 patients (93.8%) had undetectable hepatitis B virus DNA levels. Mean post-treatment ALT levels were significantly lower than mean pretreatment levels (21.3 vs 30.0 U/L, respectively; P < .001). The proportion of patients with a normal ALT was also significantly higher after versus before treatment (71.2% vs 51.2%, respectively; P = .001). The strongest factors associated with ALT abnormality after 1 year of NA treatment were body mass index (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.05-1.54; P = .01) and ozone level (OR, 1.11; 95% CI, 1.02-1.22; P = .02). Among hepatitis B e antigen-negative CHB patients with relatively low viral loads, 1 year of NA treatment improved ALT levels after the adjustment for confounding factors and increased the proportion of patients with normal ALT levels. Air pollution affects the efficacy of ALT normalization., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Autophagy has bidirectional functions in cancer by facilitating cell survival and death in a context-dependent manner. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a large family of proteins essential for numerous biological processes, including autophagy; nevertheless, their potential function in cancer malignancy remains unclear. Here, we explored the gene expression patterns of SNAREs in tissues of patients with colorectal cancer (CRC) and discovered that SEC22B expression, a vesicle SNARE, was higher in tumor tissues than in normal tissues, with a more significant increase in metastatic tissues. Interestingly, SEC22B knockdown dramatically decreased CRC cell survival and growth, especially under stressful conditions, such as hypoxia and serum starvation, and decreased the number of stress-induced autophagic vacuoles. Moreover, SEC22B knockdown successfully attenuated liver metastasis in a CRC cell xenograft mouse model, with histological signs of decreased autophagic flux and proliferation within cancer cells. Together, this study posits that SEC22B plays a crucial role in enhancing the aggressiveness of CRC cells, suggesting that SEC22B might be an attractive therapeutic target for CRC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeong-Seok Nam reports financial support was provided by the National Research Foundation of Korea through a grant funded by the Korean government and by Gwangju Institute of Science and Technology (GIST)., (Copyright © 2023. Published by Elsevier Inc.)

Background: The World Health Organization has established interim guidance for hepatitis C virus (HCV) elimination. We aimed to prove the concept of "treatment as prevention" by conducting a prospective HCV elimination program for hemodialysis (HD) patients., Methods: A universal HCV screen was launched in 22 HD centers in 2019. HCV-viremic patients were linked to care with direct-acting antivirals (DAAs). The second screen was performed in 2021 to evaluate the effect of link-to-care in lowering the prevalence of HCV viremia and the incidence of HCV new/re-infections., Results: Of 2336 patients enrolled in the first screening in 2019, 320 (13.7%) were seropositive for anti-HCV and 181 (7.7%) were HCV-viremic. Of 152 patients successfully linked to treat with DAA, 140 (92.1%) patients achieved a sustained virological response. Of them, 1733 patients participated in the second surveillance. Five anti-HCV-negative patients experienced anti-HCV seroconversion. Of 119 DAA-cured patients and 102 spontaneous HCV clearance patients, none had HCV reinfection. The annual incidence of HCV new infection was 0.1%. Sixty-one of the 620 (9.8%) newly enrolled patients were anti-HCV-seropositive in the second survey. The overall HCV-viremic rate decreased from 7.7% in 2019 to 0.6% (15/2353) in 2021. At the institutional level, 45.5% (10/22) eradicated HCV and 82% (18/22) of HD units had no HCV new infections or reinfections., Conclusions: The link-to-care project proved the concept of "treatment as prevention" by which HCV microelimination helps to prevent reinfection and new infections in the HD population.Trial registration: ClinicalTrials.gov identifier: NCT03803410 and NCT03891550., Competing Interests: M.-L.Yu.: research support from AbbVie, Abbott, BMS, Gilead, Merck and Roche. Consultant for AbbVie, Abbott, Ascletis, BMS, Gilead, J&J, Merck, Novartis, Pharmaessential and Roche. Speaker for AbbVie, Abbott, Ascletis, BMS, Gilead, Merck, Pharmaessential and Roche. C.-F.H.: speaker for AbbVie, BMS, Gilead, Merck and Roche., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background/aims: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best policies to control COVID-19 pandemic. The serological response to COVID-19 vaccination in Taiwanese patients with different comorbidities is elusive., Methods: Uninfected subjects who received 3 doses of mRNA vaccines (BNT162b2 [Pfizer-BioNTech, BNT] and mRNA-1273 [Moderna]), viral vector-based vaccines (ChAdOx1-S (AZD1222, AZ) or protein subunit vaccines (Medigen COVID-19 vaccine) were prospectively enrolled. The SARS-CoV-2-IgG spike antibody level was determined within three months after the 3rd dose of vaccination. The Charlson Comorbidity Index (CCI) was applied to determine the association between vaccine titers and underlying comorbidities., Results: A total of 824 subjects were enrolled in the current study. The proportions of CCI scores of 0-1, 2-3 and > 4 were 52.8% (n = 435), 31.3% (n = 258) and 15.9% (n = 131), respectively. The most commonly used vaccination combination was AZ-AZ-Moderna (39.2%), followed by Moderna-Moderna-Moderna (27.8%). The mean vaccination titer was 3.11 log BAU/mL after a median of 48 days after the 3rd dose. Factors associated with potentially effective neutralization capacity (IgG level ≥ 4160 AU/mL) included age ≥ 60 years (odds ratio [OR]/95% confidence interval [CI]: 0.50/0.34-0.72, P < 0.001), female sex (OR/CI: 1.85/1.30-2.63, P = 0.001), Moderna-Moderna-based vaccination (compared to AZ-AZ-based vaccination, OR/CI: 6.49/3.90-10.83, P < 0.001), BNT-BNT-based vaccination (compared to AZ-AZ-based vaccination, OR/CI: 7.91/1.82-34.3, P = 0.006) and a CCI score ≥ 4 (OR/CI: 0.53/0.34-0.82, P = 0.004). There was a decreasing trend in antibody titers with increasing CCI scores (trend P < 0.001). Linear regression analysis revealed that higher CCI scores (β: - 0.083; 95% CI: - 0.094-0.011, P = 0.014) independently correlated with low IgG spike antibody levels., Conclusions: Subjects with more comorbidities had a poor serological response to 3 doses of COVID-19 vaccination., (© 2023. The Author(s).)

Objectives: Gaps in linkage-to-care remain the barriers toward hepatitis C virus (HCV) elimination in the directly-acting-antivirals (DAA) era, especially during SARS Co-V2 pandemics. We established an outreach project to target HCV micro-elimination in HCV-hyperendemic villages., Methods: The COMPACT provided "door-by-door" screening by an "outreach HCV-checkpoint team" and an "outreach HCV-care team" for HCV diagnosis, assessment and DAA therapy in Chidong/Chikan villages between 2019 and 2021. Participants from neighboring villages served as Control group., Results: A total of 5731 adult residents participated in the project. Anti-HCV prevalence rate was 24.0% (886/3684) in Target Group and 9.5% (194/2047) in Control group (P < 0.001). The HCV-viremic rates among anti-HCV-positive subjects were 42.7% and 41.2%, respectively, in Target and Control groups. After COMPACT engagement, 80.4% (304/378) HCV-viremic subjects in the Target group were successfully linked-to-care, and Control group (70% (56/80), P = 0.039). The rates of link-to-treatment and SVR12 were comparable between Target (100% and 97.4%, respectively) and Control (100% and 96.4%) groups. The community effectiveness was 76.4% in the COMPACT campaign, significantly higher in Target group than in Control group (78.3% versus 67.5%, P = 0.039). The community effectiveness decreased significantly during SARS Co-V2 pandemic in Control group (from 81% to 31.8%, P < 0.001), but not in Target group (80.3% vs. 71.6%, P = 0.104)., Conclusions: The outreach door-by-door screen strategy with decentralized onsite treatment programs greatly improved HCV care cascade in HCV-hyperendemic areas, a model for HCV elimination in high-risk marginalized communities in SARS Co-V2 pandemic., (Copyright © 2023. Published by Elsevier B.V.)

Background: Predicting the survival of cancer patients provides prognostic information and therapeutic guidance. However, improved prediction models are needed for use in diagnosis and treatment., Objective: This study aimed to identify genomic prognostic biomarkers related to colon cancer (CC) based on computational data and to develop survival prediction models., Methods: We performed machine-learning (ML) analysis to screen pathogenic survival-related driver genes related to patient prognosis by integrating copy number variation and gene expression data. Moreover, in silico system analysis was performed to clinically assess data from ML analysis, and we identified RABGAP1L, MYH9, and DRD4 as candidate genes. These three genes and tumor stages were used to generate survival prediction models. Moreover, the genes were validated by experimental and clinical analyses, and the theranostic application of the survival prediction models was assessed., Results: RABGAP1L, MYH9, and DRD4 were identified as survival-related candidate genes by ML and in silico system analysis. The survival prediction model using the expression of the three genes showed higher predictive performance when applied to predict the prognosis of CC patients. A series of functional analyses revealed that each knockdown of three genes reduced the protumor activity of CC cells. In particular, validation with an independent cohort of CC patients confirmed that the coexpression of MYH9 and DRD4 gene expression reflected poorer clinical outcomes in terms of overall survival and disease-free survival., Conclusions: Our survival prediction approach will contribute to providing information on patients and developing a therapeutic strategy for CC patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Thought-action fusion (TAF), which is a tendency to make the relationship between one's thoughts and external consequences, is a dysfunctional belief linked to obsessive-compulsive disorder (OCD). While the TAF is commonly evaluated using the Thought-Action Fusion Scale (TAFS), it cannot fully reflect the actual experience of experimentally evoked TAF. In the present study, we applied a multiple-trial version of the classic TAF experiment and evaluate two variables, reaction time (RT) and emotional intensity (EI)., Methods: Ninety-three patients with OCD and 45 healthy controls (HCs) were recruited. The participants were asked to read the name of a close or neutral person embedded in different positive (PS) or negative (NS) TAF statements. During the experiments, RT and EI were gathered., Results: The OCD patients presented with longer RT and lower EI in the NS condition than HCs. In each group, the HCs showed a significant relationship between RT in the NS condition and TAFS scores, whereas the patients did not, although they had higher TAFS scores than the HCs. In contrast, the patients showed a trend toward a correlation between RT in the NS condition and guilt., Conclusion: These findings may indicate our multiple-trial version of the classical TAF showed reliable results of the two new variables, especially RT, in the task and allow to newly identify paradoxical patterns in which the TAFS scores are high but actual performance is impaired, that is, the inefficient activation of TAF in OCD.

Successful eradication of the hepatitis C virus (HCV) cannot eliminate the risk of hepatocellular carcinoma (HCC). Next-generation RNA sequencing provides comprehensive genomic insights into the pathogenesis of HCC. Artificial intelligence has opened a new era in precision medicine. This study integrated clinical features and genetic biomarkers to establish a machine learning-based HCC model following viral eradication. A prospective cohort of 55 HCV patients with advanced fibrosis, who achieved a sustained virologic response after antiviral therapy, was enrolled. The primary outcome was the occurrence of HCC. The genomic signatures of peripheral blood mononuclear cells (PBMC) were determined by RNA sequencing at baseline and 24 weeks after end-of-treatment. Machine learning algorithms were implemented to extract the predictors of HCC. HCC occurred in 8 of the 55 patients, with an annual incidence of 2.7%. Pretreatment PBMC DEFA1B, HBG2, ADCY4, and posttreatment TAS1R3, ABCA3, and FOSL1 genes were significantly downregulated, while the pretreatment ANGPTL6 gene was significantly upregulated in the HCC group compared to that in the non-HCC group. A gene score derived from the result of the decision tree algorithm can identify HCC with an accuracy of 95.7%. Gene score = TAS1R3 (≥0.63 FPKM, yes/no = 0/1) + FOSL1 (≥0.27 FPKM, yes/no = 0/1) + ABCA3 (≥2.40 FPKM, yes/no = 0/1). Multivariate Cox regression analysis showed that this gene score was the most important predictor of HCC (hazard ratio = 2.38, 95% confidence interval [CI] = 1.06-5.36, P = 0.036). Combining the gene score and fibrosis-4 index, a nomogram was constructed to predict the probability of HCC with an area under the receiver operating characteristic curve up to 0.950 (95% CI = 0.888-1.000, P = 7.0 × 10 -5 ). Decision curve analysis revealed that the nomogram had a net benefit in HCC detection. The calibration curve showed that the nomogram had optimal concordance between the predicted and actual HCC probabilities. In conclusion, down-regulated posttreatment PBMC TAS1R3, ABCA3, and FOSL1 expression were significantly correlated with HCC development after HCV eradication. Decision-tree-based algorithms can refine the assessment of HCC risk for personalized HCC surveillance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (AJCR Copyright © 2023.)

Lenvatinib has been effective not only as a first-line but also as a later-line systemic therapy for unresectable hepatocellular carcinoma (uHCC) in real-world clinical practice. How to predict the efficacy of lenvatinib and guide appropriate therapy selection in patients with uHCC have become important issues. This study aimed to investigate the impact of serum biomarkers on the treatment outcomes of patients with uHCC treated with lenvatinib in a real-world setting using an artificial intelligence algorithm. We measured serum biomarkers, including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, and circulating angiogenic factors (CAFs [i.e., vascular endothelial growth factor, angiopoietin-2, fibroblast growth factor-19 [FGF19], and FGF21]) and analyzed treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with uHCC treated with lenvatinib. The results of this study demonstrated that an AFP reduction ≥ 40% from baseline within 8 weeks after lenvatinib induction was associated with a higher ORR. With baseline biomarkers using a decision tree-based model, we identified patients with high, intermediate, and low ORRs (84.6%, 21.7% and 0%, respectively; odds ratio, 53.04, P < 0.001, high versus intermediate/low groups). Based on the decision tree-based survival predictive model, baseline AFP was the most important factor for OS, followed by ALBI grade and FGF21., Competing Interests: Ming-Lung Yu has served as a speaker for AbbVie, Abbott, Bristol-Myers Squibb, Gilead, Merck, a consultant for AbbVie, Abbott, Bristol-Myers Squibb, Gilead, Merck and PharmaEssentia, and has received research funding from AbbVie, Abbott, Bristol-Myers Squibb, Gilead, and Merck. Chung-Feng Huang has served as a speaker for AbbVie, Bristol-Myers Squibb, Gilead, Merck, and Roche. Jee-Fu Huang has served as a speaker for AbbVie, Bristol-Myers Squibb, Gilead, Merck, Sysmex, Roche, a consultant for Roche, Bristol-Myers Squibb, Gilead, Merck, Sysmex, PharmaEssentia, and Polaris Pharmaceuticals., (AJCR Copyright © 2022.)

The high accessibility to healthcare and increasing awareness of hepatocellular carcinoma (HCC) surveillance after sustained virologic response (SVR) to HCV treatment allow early detection of operable HCC in Taiwan. However, the effects of achieving SVR on patient characteristics and surgical outcomes after curative resection remain elusive. We aimed to compare the clinical presentation and postoperative prognosis among patients with early-stage HCV-related HCC and different viral status. We retrospectively analyzed 208 patients with BCLC stage 0 or A-HCC, including 44 patients who remained HCV viremic, 90 patients who developed HCC after achieving SVR (post-SVR HCC), and 74 patients who subsequently achieved SVR after resection. Patients with post-SVR HCC had a lower degree of hepatitis and better liver function than those who achieved SVR or remained viremic after resection. Notably, 75.6% of patients with post-SVR HCC did not have cirrhosis. Patients with post-SVR HCC and those achieving SVR after resection exhibited comparable recurrence rates and recurrence-free survival, while patients with persistent viremia had the worst surgical outcomes. We concluded that patients with post-SVR HCC had a better liver function but similar surgical outcomes compared with patients who achieved SVR after resection. The low prevalence of cirrhosis in patients with post-SVR HCC highlights the importance of regular surveillance after SVR.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a promising serum marker for hepatocellular carcinoma (HCC). There are limited data on its cutoff value in HCC for Taiwanese cirrhosis patients. This study aimed to investigate the diagnostic value of PIVKA-II levels in patients with suspected HCC. In total, 88 patients with chronic hepatitis and suspected HCC by ultrasound, elevated α-fetoprotein (AFP) or PIVKA-II levels were consecutively enrolled. Their baseline characteristics and findings on dynamic phases of computed tomography (CT) or magnetic resonance imaging (MRI) were examined. Sixty participants had cirrhosis and 34 had HCC. The median levels of PIVKA-II in non-cirrhosis and cirrhosis patients without or with HCC were 28.0, 48.0, and 847.0 mAU/mL, respectively. The optimal cutoff value of PIVKA-II in predicting HCC was 78.0 mAU/mL. Combining AFP with PIVKAII mildly increased its diagnostic performance for HCC, yielding higher specificity and positive predictive value. Significant factors predicting HCC in multivariate regression analysis were PIVKA >78.0 mAU/mL and fatty liver. Monitoring PIVKA-II level is suitable for noninvasively assessing HCC in patients with chronic hepatitis, particularly with AFP., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: An outbreak of SARS-CoV-2 Delta variant infection occurred in Pingtung, Taiwan, in June 2021. In this study, we aimed to elucidate the clinical characteristics of the Delta-variant SARS-CoV-2 infection and the treatment outcome of antiviral agents in patients from Pingtung County in Southern Taiwan., Methods: A total of 11 patients with Delta-variant COVID-19 were consecutively admitted to a governmental hospital in June 2021. Baseline characteristics and treatment outcome were evaluated., Results: All patients were symptomatic. The most common symptoms were cough (72.7%), followed by fever (54.5%), headache (18.2%) and dysosmia/dysgeusia (18.2%). Two patients developed pneumonia without mechanical ventilation requirement. Compared to patients without pneumonia, those with pneumonia had higher aspartate aminotransferase (AST) (21.0 vs. 126.0 IU/L, P = 0.03) and lactate dehydrogenase (LDH) (143.1 vs. 409.0 IU/mL, P = 0.03), and ferritin (0.2 vs. 2.0 mg/L, P = 0.046) levels. Pneumonia improved after 2-week treatment, and no mortality occurred after 30 days of diagnosis. The median duration of viral shedding duration of viral shedding was 16.5 days (range 11-42 days) (defined by time to repeated negative real-time reverse transcriptase polymerase chain reaction (RT-PCR) or a cycle threshold (CT) value ≥ 30)., Conclusion: We demonstrated the clinical characteristics of Delta-variant COVID-19 and treatment outcome of antiviral agents. The risk factors attributed to pneumonia were higher serum AST, ferritin, and LDH levels., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) eradication through antivirals ameliorates metabolic profiles. The changes in 2-h plasma glucose (2HPG) levels by oral glucose tolerance test (OGTT), in chronic hepatitis C (CHC) patients who receive directly acting antivirals (DAAs) was elusive. Five hundred and thirty-three CHC patients who achieved sustained virological response (SVR, undetectable HCV RNA throughout 3 months after the end-of-treatment) by DAAs were consecutively enrolled. Pre- and posttreatment 2HPG levels and glucose status were compared. The proportion of patients with improved, worsened, and stable 2HPG was 14.4% (n = 77), 18.6% (n = 99), and 67.0% (n = 357), respectively. Compared with patients with worsening 2HPG, those with improved 2HPG had a higher proportion of cirrhosis (45.5% vs. 24.2%, p = 0.004) and higher pretreatment 2HPG levels (175.3 vs. 129.5 mg/dl, p < 0.001). High baseline 2HPG was independently associated with improved 2HPG in multivariate analysis (odds ratio [OR]/CI: 1.05/1.03-1.06, p < 0.001). When baseline 2HPG was not taken into account, cirrhosis was the only factor independently associated with improved 2HPG status (OR/CI: 2.58/1.29-5.15, p = 0.007). Linear regression analysis revealed that factors independently correlated to changes in 2HPG levels were female sex (β: 8.78; 95% CI:2.34, 15.22; p = 0.01), diabetes (β: -27.72; 95% CI: -50.16, -5.28; p = 0.02), liver cirrhosis (β: -8.91; 95% CI: -16.75, -2.20; p = 0.01), and genotype 1 of HCV (β: -0.12; 95% CI: -15.19, -2.43; p = 0.01). 2HPG improved after HCV eradication by DAAs, particularly in cirrhotic patients., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Objective: Recent studies highlighted the triple-network model which illustrated the interactions among three large-scale networks including salience network (SN). The functional magnetic resonance imaging used in this study was designed to investigate the characteristics of three large-scale networks associated with the thought-action fusion (TAF) in patients with obsessive-compulsive disorder (OCD) using power spectral density (PSD) analysis., Methods: This study included 32 OCD patients and 38 age-matched healthy controls (HC). The TAF task was modified from the experiment of Rassin. PSD from time courses in large-scale networks of each subject was measured to compare between the groups for both TAF and resting state., Results: In SN, OCD reported lower power in the low-frequency domain of SN compared to HC using the two-sample t test during the TAF task (t = -2.395, p = 0.019) but not in the resting state. The PSD in the low-frequency domain of the SN had a significant negative correlation with state score in the guilty inventory (r = -0.361, p = 0.042) in OCD patients., Conclusion: This study suggests that OCD patients showed reduced SN power which can be prominent in a certain situation, such as TAF. In addition, the PSD alterations in SN cause difficulty in processing ambiguous emotional cues in social situations, and the difficulty can be connected with a negative feeling (e.g., guilt).

Background: Cognitive theories of obsessive-compulsive disorder (OCD) stress the importance of dysfunctional beliefs in the development and maintenance of the disorder. However, a neurobiological understanding of these cognitive models, including thought-action fusion (TAF), is surprisingly lacking. Thus, this functional magnetic resonance imaging study aimed to investigate whether altered functional connectivity (FC) is associated with the TAF paradigm in OCD patients., Methods: Forty-one OCD patients and 47 healthy controls (HCs) participated in a functional magnetic resonance imaging study using a TAF task, in which they were asked to read the name of a close or a neutral person in association with positive and negative statements., Results: The conventional TAF condition (negative statements/close person) induced significant FC between the regions of interest (ROIs) identified using multivoxel pattern analysis and the visual association areas, default mode network subregions, affective processing, and several subcortical regions in both groups. Notably, sparser FC was observed in OCD patients. Further analysis confined to the cortico-striato-thalamo-cortical (CSTC) and affective networks demonstrated that OCD patients exhibited reduced ROI FC with affective regions and greater ROI FC with CSTC components in the TAF condition compared to HCs. Within the OCD patients, middle cingulate cortex-insula FC was correlated with TAF and responsibility scores., Conclusions: Our TAF paradigm revealed altered context-dependent engagement of the CSTC and affective networks in OCD patients. These findings suggest that the neurobiology of cognitive models corresponds to current neuroanatomical models of OCD. Further, they elucidate the underlying neurobiological mechanisms of OCD at the circuit-based level.

Rationale: Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that selectively marks cancer stem-like cells (CSCs) and promotes malignant progression in colorectal cancer (CRC). However, the exact molecular mechanism by which DCLK1 drives the aggressive phenotype of cancer cells is incompletely determined. Methods: Here, we performed comprehensive genomics and proteomics analyses to identify binding proteins of DCLK1 and discovered X-ray repair cross-complementing 5 (XRCC5). Thus, we explored the biological role and downstream events of the DCLK1/XRCC5 axis in human CRC cells and CRC mouse models. Results: The results of comprehensive bioinformatics analyses suggested that DCLK1-driven CRC aggressiveness is linked to inflammation. Mechanistically, DCLK1 bound and phosphorylated XRCC5, which in turn transcriptionally activated cyclooxygenase-2 expression and enhanced prostaglandin E 2 production; these events collectively generated the inflammatory tumor microenvironment and enhanced the aggressive behavior of CRC cells. Consistent with the discovered mechanism, inhibition of DCLK1 kinase activity strongly impaired the tumor seeding and growth capabilities in CRC mouse models. Conclusion: Our study illuminates a novel mechanism that mediates the pro-inflammatory function of CSCs in driving the aggressive phenotype of CRC, broadening the biological function of DCLK1 in CRC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Understanding the barriers and tackling the hurdles of hepatitis C virus (HCV) care cascades is key to HCV elimination. The current study aimed to investigate the rates of disease awareness, link-to-care, and treatment uptake of HCV in a hyperendemic area in Taiwan. Tzukuan residents from 2000 to 2018 were invited to participate in the questionnaire-based interviews for HCV. The rates of disease awareness, accessibility, and anti-HCV therapy were evaluated in anti-HCV-seropositive participants. Among 10,348 residents, 1789 (17.3%) were anti-HCV seropositive. Of these 1789 anti-HCV-seropositive participants, data of 594 participants from questionnaire-based interviews in 2005-2018 were analyzed for HCV care cascades. Overall, 24.9% of anti-HCV-seropositive HCV participants had disease awareness, 53.9% of aware participants had accessibility, and 79.8% of assessed participants had received HCV treatment, with a community effectiveness of 10.7%. HCV prevalence decreased over time, from 21.2% in the early cohort to 9.3% in the recent cohort. Disease awareness increased over time, from 15.6% to 41.7%, with the community effectiveness increasing from 1.3% to 28.8%. Lower education levels and normal liver biochemistry were associated with a lower rate of disease awareness. Notably, 68% of participants with abnormal liver biochemistry and 69% of those with advanced fibrosis (FIB-4 > 3.25) were unaware of their HCV disease. We demonstrated huge gaps in disease awareness, link-to-care, and treatment uptake in the HCV care cascade in an HCV-hyperendemic area, even in the initial era of direct-acting antiviral agents. There is an urgent need to overcome these hurdles to achieve HCV elimination., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Chronic hepatitis B (CHB) patients with low disease activity are at risk of liver fibrosis. The age-adjusted fibrosis-4 index (FIB4-AA), developed in our previous publication, and was implemented to evaluate the tendency of liver fibrosis in these patients. We aimed to investigate the rate of liver fibrosis in CHB patients with low disease activity. Resuming our previous study, the FIB-4 changes of 244 antiviral treatment-naïve CHB patients, with a total of 1243.48 person-years, were reviewed. Among the cohort, patients were categorized as FIB4-AA positive or negative according to the results of their last FIB4-AA minus their initial FIB-4 during at least 18 months of observation time. The compound annual growth rate (CAGR) of FIB-4 was calculated for the FIB4-AA positive and negative groups. The assumed healthy controls had an FIB-4 CAGR calculated to be 2.34% for both men and women, while the FIB-4 CAGR of the whole study cohort was 2.84% ± 6.01%. FIB4-AA positive effectively identifies CHB patients with higher mean FIB-4 CAGR (7.11% ± 3.88% vs. -2.36% ± 3.52%, p < 0.0001). Overweight CHB patients had 10 times smaller mean FIB-4 CAGR than lean ones (0.38% ± 10.35% vs. 3.83% ± 8.88%, p = 0.009). An increase in FIB4-AA over at least 18 months in CHB patients with relatively low disease activity meant they were at greater risk of liver fibrosis, and these patients had a mean FIB-4 CAGR of 7.11%. The FIB-4 CAGR was compatible with the findings of previous studies on the collagen proportionate area in viral hepatitis patients., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Rationale : Dysadherin is a tumor-associated, membrane-embedded antigen found in multiple types of cancer cells, and associated with malignant behavior of cancer cells; however, the fundamental molecular mechanism by which dysadherin drives aggressive phenotypes of cancer is not yet fully determined. Methods : To get a mechanistic insight, we explored the physiological relevance of dysadherin on intestinal tumorigenesis using dysadherin knockout mice and investigated its impact on clinicopathological features in patients with advanced colorectal cancer (CRC). Next, to discover the downstream signaling pathways of dysadherin, we applied bioinformatic analysis using gene expression data of CRC patient tumors and dysadherin knockout cancer cells. Additionally, comprehensive proteomic and molecular analyses were performed to identify dysadherin-interacting proteins and their functions. Results : Dysadherin deficiency suppressed intestinal tumorigenesis in both genetic and chemical mouse models. Moreover, increased dysadherin expression in cancer cells accounted for shorter survival in CRC patients. Comprehensive bioinformatics analyses suggested that the effect of dysadherin deletion is linked to a reduction in the extracellular matrix receptor signaling pathway. Mechanistically, the extracellular domain of dysadherin bound fibronectin and enhanced cancer cell adhesion to fibronectin, facilitating the activation of integrin-mediated mechanotransduction and leading to yes-associated protein 1 activation. Dysadherin-fibronectin interaction promoted cancer cell growth, survival, migration, and invasion, effects collectively mediated the protumor activity of dysadherin. Conclusion : Our results highlight a novel function of dysadherin as a driver of mechanotransduction that stimulates CRC progression, providing a potential therapy strategy for CRC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The role of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA + -M2BP) in the prediction of disease severity in nonalcoholic fatty liver disease (NAFLD) remains elusive. This study evaluated the performance of WFA + -M2BP in predicting fibrosis in patients with NAFLD. A total of 80 patients with biopsy-proven nonalcoholic steatohepatitis (NASH) were enrolled. Serum WFA + -M2BP levels were measured using standard methods. The fibrosis-4 (FIB-4) index was also measured. The mean values of WFA + -M2BP were 1.0, 1.0, 0.8, and 2.2 in Metavir fibrosis stage F0, F1, F2, and F3-4, respectively (linear trend p = 0.005). The optimal cut-off value of WFA + -M2BP in predicting advanced fibrosis (F3-4) was 1.37 cut-off index (COI), yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of 75.0, 79.4, 39.1, 94.7, and 78.7%, respectively (p < 0.001). Combining WFA + -M2BP with FIB-4 significantly increased the diagnostic performance for advanced fibrosis, yielding specificity, PPV, and accuracy of 100, 100, and 93%, respectively. The significant factors predicting advanced liver fibrosis in the multivariate regression analysis were WFA + -M2BP ≥ 1.37 COI (OR/confidence interval [CI]: 9.49/1.63-55.21, p = 0.01) and FIB-4 ≥ 2.80 (OR/CI: 38.18/4.89-297.93, p = 0.001). Monitoring WFA + -M2BP is suitable for noninvasive assessment of liver fibrosis in NASH patients, particularly in combination with FIB-4., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background and Aims: The itemization difference of patient-reported outcome (PRO) in hepatitis patients with different etiologies remains elusive in Asia. We aimed to assess the characteristics and the difference of health-related quality of life (HRQoL) in chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) patients., Methods: We conducted the study in an outpatient setting. The 36-Item Short Form Health Survey (SF-36) was completed by the patients upon the initial diagnosis and recruitment for a long-term follow-up purpose. The PRO results were also assessed by disease severity., Results: There were 244 patients (198 males) of CHB, 54 patients (29 males) of CHC, and 129 patients (85 males) of NAFLD, respectively. CHC patient had the mean score of 67.1 ± 23.3 in physical component summary (PCS) of the SF-36 health survey, which was significantly lower than CHB patients (76.4 ± 19.5), and NAFLD patients (77.5 ± 13.7), respectively (p = 0.001). The significantly lower performance of PCS in CHC patients was mainly attributed to the lower performance in physical functioning and bodily pain components. Higher fibrosis 4 index scores were significantly associated with lower PCS scores in all patient groups. There was no significant difference of mean mental component summary (MCS) between groups. However, NAFLD patients had significantly lower mental health scores than other groups (p = 0.02)., Conclusions: The significant difference of HRQoL exists in hepatitis patients with different etiologies. Disease severity leads to a lower PCS performance., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Scarce data are available on in-hospital hepatitis C virus (HCV) micro-elimination strategies. This pilot study was prospectively conducted to assess the outcomes of HCV in-hospital micro-elimination program (HCV-HELP) in a single center in Taiwan., Methods: The study included the HCV reflex test for plans A (hospital personnel), B (outpatient surveillance), C (a call-back system for anti-HCV+ patients), and D (surveillance of cancer patients prior to chemotherapy). The primary outcome measurement was that > 80% of eligible patients were enrolled in linkage-to-treat; the secondary outcome measurement was the surveillance efficacy., Results: We recruited 930, 6072, 2376 and 233 participants into plans A, B, C, and D, respectively, from Oct 2020 to May 2021. The anti-HCV-seropositivity prevalences were 0.22% for plan A, 4.3% for B, and 3.9% for D. Two staff members were identified as HCV-viremic in plan A; these staff members successfully achieved a sustained virological response (SVR). We identified 39, 95 and 2 HCV-viremic patients in plans B, C, and D, respectively. Of these 138 HCV-viremic patients, 135 (97.8%) received direct-acting antiviral therapy, and 134 achieved SVR. Two 4-month phases were stratified to compare efficacies in the liver clinic. In the late phase, the adjusted number of HCV-viremic patients was 4.36/10,000 outpatient visits (90/200,689), which was 3.18-fold higher than that of the early phase (1.37/10,000 outpatient visits [30/212,658], odds ratio 3.18; 95% confidence interval 2.10-4.81, p < 0.0001)., Conclusion: HCV micro-elimination is achievable at the hospital level as per the structured HCV-HELP study., (© 2021. Asian Pacific Association for the Study of the Liver.)

Background: Prisoners are at risk of hepatitis C virus (HCV) infection, especially among the people who inject drugs (PWID). We implemented an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic direct-acting antivirals (DAA) regimen, 12 wk of sofosbuvir/velpatasvir, in a PWID-dominant prison in Taiwan., Aim: To implement an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic DAA regimen in a PWID-dominant prison in Taiwan., Methods: HCV-viremic patients were recruited for onsite treatment program for HCV micro-elimination with a pangenotypic DAA regimen, 12 wk of sofosbuvir/ velpatasvir, from two cohorts in Penghu Prison, either identified by mass screen or in outpatient clinics, in September 2019. Another group of HCV-viremic patients identified sporadically in outpatient clinics before mass screening were enrolled as a control group. The primary endpoint was sustained virological response (SVR12, defined as undetectable HCV ribonucleic acid (RNA) 12 wk after end-of-treatment)., Results: A total of 212 HCV-viremic subjects were recruited for HCV micro-elimination campaign; 91 patients treated with sofosbuvir/Ledipasvir or glecaprevir/ pibrentasvir before mass screening were enrolled as a control. The HCV micro-elimination group had significantly lower proportion of diabetes, hypertension, hyperlipidemia, advanced fibrosis and chronic kidney diseases, but higher levels of HCV RNA. The SVR12 rate was comparable between the HCV micro-elimination and control groups, 95.8% (203/212) vs 94.5% (86/91), respectively, in intent-to-treat analysis, and 100% (203/203) vs 98.9% (86/87), respectively, in per-protocol analysis. There was no virological failure, treatment discontinuation, and serious adverse event among sofosbuvir/velpatasvir-treated patients in the HCV micro-elimination group., Conclusion: Outreach mass screening followed by immediate onsite treatment with a simplified pangenotypic DAA regimen, sofosbuvir/velpatasvir, provides successful strategies toward HCV micro-elimination among prisoners., Competing Interests: Conflict-of-interest statement: No author had reported a potential conflict of interest relevant to this work., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Chronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development., Aim: To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy., Methods: One hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment., Results: HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively., Conclusion: Downregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients., Methods: We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020., Results: Eighty-six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6-4.6). The most frequently reported adverse events were hand-foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8-17.0) and the median progression-free survival (PFS) was 4.2 months (95% CI, 3.7-4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP < 400 ng/ml exhibited a markedly longer median OS, median PFS, and higher DCR compared with their counterparts (15.7 vs. 8.1 months, 4.6 vs. 3.7 months, 60.9% vs. 27.5%, respectively). Despite possessing high baseline AFP levels, patients with early AFP response (>10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP < 400 ng/ml., Conclusions: The results of this real-world study verified the tolerability and efficacy of regorafenib treatment for uHCC patients who failed prior sorafenib therapy, especially for those with lower baseline AFP levels or with early AFP response., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background & Aims: Gamma-glutamyl transferase (GGT) has been predictive of chronic hepatitis C-related hepatocellular carcinoma (HCC) development. Its role in the risk of HCC in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs) is elusive., Methods: A total of 2172 CHB patients from East Asia were randomized into development and validation groups in a 1:2 ratio. Serum GGT levels before and 6 months (M6) after initiating NAs and the potential risk factors were measured. The primary endpoint was HCC development 12 months after NA initiation., Results: The annual incidence of HCC was 1.4/100 person-years in a follow-up period of 11 370.7 person-years. The strongest factor associated with HCC development was high M6-GGT levels (>25 U/L; hazard ratio [HR]/95% confidence interval [CI]: 3.31/2.02-5.42, P < .001), followed by cirrhosis (HR/CI: 2.06/1.39-3.06, P < .001), male sex (HR/CI: 2.01/1.29-3.13, P = .002) and age (HR/CI: 1.05/1.03-1.17, P < .001). Among cirrhotic patients, the incidence of HCC did not differ between those with high or low M6-GGT levels (P = .09). In contrast, among non-cirrhotic patients, the incidence of HCC was significantly higher for those with M6-GGT level >25 U/L than for their counterparts (P < .001). Cox regression analysis revealed that the strongest factor associated with HCC development in non-cirrhotic patients was high M6-GGT levels (HR/CI: 5.05/2.52-10.16, P < .001), followed by age (HR/CI: 1.07/1.04-1.09, P < .001). Non-cirrhotic elderly patients with high M6-GGT levels had a similarly high HCC risk as cirrhotic patients did (P = .29)., Conclusions: On-treatment serum GGT levels strongly predicted HCC development in CHB patients, particularly non-cirrhotic patients, treated with NAs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)